Structure-activity studies with fragments and analogous of salmonid melanin-concentrating hormone

A number of cyclic and linear fragments and analogues of MCH were synthesized and their biological potencies tested using the isolated carp scale melanophore assay. In this system the cyclic portion MCH(5-14) exhibited only 0.1% bioactivity, which was markedly enhanced by the addition of the exocyclic sequences MCH(15-17) and MCH(1-4). The exocyclic sequence itself, MCH(1-4,15-17), had minimal activity, however. Substitution of Tyr11 with phenylalanine reduced the potency of the ring structure MCH(5-14) by about 4-fold. Substitution of Gly8 with D-alanine reduced the potency of MCH(5-14) 16-fold, while both substitutions together caused a still more marked reduction (200-fold) in bioactivity. Linearized fragments of MCH, extending from MCH(15-17) to [Cys(Acm)5,14]MCH(1-17), showed a progressive increase in potency. The linearized forms of MCH, MCH(5-17) and MCH(5-14), were approximately 100-fold or less potent than their cyclic forms. The significant increases in bioactivity produced by the addition of the C- and N-terminal exocyclic sequence even to these linearized forms further emphasizes the importance of these regions for interaction at the receptor site.